The hippocampal-prefrontal circuit is implicated in many neuropsychiatric illnesses. This circuit is critically involved in multiple aspects of cognition and emotional regulation, and is particularly vulnerable to stress, which is a key precipitating factor for many of these disorders. Chronic stress can have deleterious effects on neuronal structure and physiological function in the hippocampus, and impair hippocampal-dependent behavior, including processing of contextual fear memories. The hippocampus and prefrontal cortex communicate during cognitive and emotional tasks by altering the coherence of oscillatory activity between the two regions. However, the cellular and molecular events that drive these changes in hippocampal-prefrontal synchrony, and how they are influenced by stress, are not well understood. Understanding the mechanisms by which exposure to stress leads to disruptions in hippocampal-prefrontal interactions during fear regulation is a high priority given that altered fear-related behavior is prominent in many neuropsychiatric disorders. Our preliminary data support the hypothesis that exposure to stress impacts plasticity in the hippocampal-prefrontal pathway, leading to disrupted connectivity between the two regions and enhanced fear-related behavior. Many of the risk factors for neuropsychiatric disorders, including stress, affect genes that play important roles in the development and plasticity of synapses. Hence, disruptions in synaptic connections of the long-range projections between the hippocampus and prefrontal cortex could contribute to impairments in hippocampal-prefrontal synchrony. However, there is a dearth of research aimed at understanding molecular signaling pathways in these projection cells. The central hypothesis of this proposal is that defined programs of cellular and molecular signaling in hippocampal-prefrontal projection neurons control their structure and function, and that these signaling pathways regulate patterns of neural activity and connectivity between the two structures. The overall goals of this application are to 1) understand how stress drives molecular and cellular signaling in hippocampal-prefrontal projection cells to control their physiological function; and 2) determine how plasticity in hippocampal-prefrontal projections neurons impacts functional connectivity in this circuit to control fear-related behavior. We use a technically sophisticated combination of neuronal morphology analysis with endoscopic imaging and in vivo electrophysiology to understand how stress impacts cellular plasticity in hippocampal-prefrontal projection neurons. We then determine how these cellular correlates of plasticity impact hippocampal-prefrontal synchrony during fear-related behavior. In addition to cellular correlates, we combine molecular profiling techniques with retrograde viral approaches to investigate molecular contributions to plasticity in hippocampal-prefrontal neurons. The research will reveal fundamental information about molecular and cellular signaling programs in hippocampal-prefrontal projection neurons that contribute to functional connectivity, information that will be critical for future strategies targeting this pathway.